The protein known as the human homolog of the Drosophila KUZ gene is a member of the ADAM family of metalloproteases. This protease and another family member, TNF converting enzyme, have been shown to be capable of processing pro-TNF to the mature form of TNF (Black et al. Nature 385:729, 1997; Lunn et al., FEBS Lett. 400: 333-335, 1997). Therefore, this and additional family members would be expected to have a role in the processing of other cytokines, growth factors, or receptors. Other cytokines or receptors in which processing occurs and in which the biochemistry is consistent with a mechanism involving ADAM family members include CD23, L-selectin, FAS ligand, CD16 and others (reviewed in Hooper et al., Biochem J. 321, 265-279, 1997). The relationship between the possible substrates and ADAM family members is unknown, so that human KUZ protein may participate in the processing of any combination of these cytokines and growth factors in one or more cell types. Other family members, meltrin and fertilin, are involved in cell-cell fusion (Yagami-Hiromasa et al. Nature 377: 652-656 (1995). The bovine homolog of the human KUZ protein has been shown to use myelin as a substrate (Howard et al., Biochem J. 317: 45-50, 1996) and the Drosophila KUZ gene product is involved in neural differentiation (Rooke et al. Science 273: 1227-1231, 1996). Inhibition of one or more of these processing enzymes could have therapeutic utility in inflammation, neural degeneration, allergic disorders, or other disorders involving a dis-regulation of the substrate cytokines or receptors.
This indicates that the ADAM family has an established, proven history as therapeutic targets. Clearly there is a need for identification and characterization of further members of the ADAM family which can play a role in preventing, ameliorating or correcting dysfunctions or diseases, including, but not limited to, inflammation, neural degeneration, allergic disorders, or other disorders involving a dis-regulation of the substrate cytokines or receptors.